Combination

ABSTRACT

The invention relates to the combined administration of PDE4 or PDE3/4 inhibitors and leukotriene receptor antagonists for the treatment of respiratory tract disorders.

FIELD OF APPLICATION OF THE INVENTION

The present invention relates to combinations of pharmaceutically activesubstances for use in the treatment of respiratory tract disorders.

The substances used in the combinations according to the invention areknown active compounds from the PDE4 and PDE3/4 inhibitors class andactive compounds from the class of the leukotriene receptor antagonists.

KNOWN TECHNICAL BACKGROUND

In the International Patent Application WO02/38155 the combined use ofRoflumilast, Roflumilast-N-Oxide or a pharmaceutically acceptable saltof either compound on the one hand and of a leukotriene-receptorantagonist on the other hand for the treatment of bronchial andrespiratory disorders is described. In the International PatentApplication WO01/90076 a pharmaceutical composition comprisingRoflumilast-N-Oxide and a leukotriene receptor antagonist is claimed.

DESCRIPTION OF THE INVENTION

Asthma is a common inflammatory disease of the respiratory tract,accounting for 1-3% of all office visits, 500,000 hospital admissionsper year and more pediatric hospital admissions than any other singleillness in the US. Annually, more than 5000 children and adults die ofasthma attacks in the United States (William E. S.; Goodmann GilmannA.:The pharmacological Basis of Therapeutics, 9^(th) Edition, pp. 152 &659-682, Mc Graw Hill, New York 1996).

Asthma can no longer be viewed simply as a reversible airwayobstruction. It should instead be considered primarily as aninflammatory illness that has bronchial hyperactivity and bronchospasmas its results. Allergen specific immunoglobulin E (IgE) is bound to themast cells via Fc receptors. It is a fragment obtained by papaindigestion of immunoglobulin molecules and contains most of the antigenicdeterminants. When an allergen comes into contact with IgE, the mastcells are activated and release a number of inflammatory mediators,which include granule contents like histamine, proteases, heparin, andtumor necrosis factor (TNF), a variety of lipid membrane derivedmolecules like prostaglandins, leukotrienes and platelet activatingfactor (PAF), and a number of cytokines like interleukin (IL)-1, 3, 4,5, 6 and 8 and chemokines. An enormous variety of mediators are releasedwhich have more than one potent effect on airway inflammation.

As a result of vasodilation, increased vasopermeability and increasedendothelial adhesiveness towards leukocytes further leads to an influxof inflammatory cells like lymphocytes, eosinophils and macrophages fromblood circulation into the tissues. This in turn leads to the release ofmediators which have further inflammatory effects (Rao A. R. et al.Recent Perspectives in the design of antiasthmatic agents, Pharmazie,55, 7, 475-482, 2000).

Thus, it can be understood that it is unlikely that drugs affecting asingle mediator can satisfactorily treat the disease alone. As asthma isone of the major diseases affecting mankind, there is a need to developdrugs which can affect a wide variety of mediators.

Therefore, it is the object of the present invention to make availablerespiratory tract therapeutics which fulfil the following conditions:

-   -   Favorable simultaneous influence on several of the inflammatory        mediators    -   Marked bronchorelaxation and -dilatation    -   Good oral availability    -   Minor side effects    -   Good suitability for long-term therapy    -   Favorable influence on bronchial hyperreactivity

It has now been found that the combined use of a PDE4 or a PDE3/4inhibitor and a leukotriene receptor antagonist outstandingly fulfillsthe above-mentioned conditions.

The invention thus relates to the combined use of a PDE4 or a PDE3/4inhibitor and a leukotriene receptor antagonist in the treatment ofrespiratory tract disorders.

“Combined use” in the context of the invention means the simultaneous,sequential or separate administration of the PDE4 or the PDE3/4inhibitor on the one hand and of the leukotriene receptor antagonist onthe other hand.

Simultaneous administration includes—aside from the simultaneous uptakeof two separate dosage forms containing the PDE4 or the PDE3/4 inhibitorin the one and the leukotriene receptor antagonist in the other dosageform—pharmaceutical compositions containing both active ingredients inone single dosage form (fixed unit dose form).

Sequential administration in the context of the invention means theadministration of the PDE4 or the PDE3/4 inhibitor on the one hand andof the leukotriene receptor antagonist on the other hand in separatedosage forms within less than 12 hours, more preferably within less thanone hour, most preferably within 5 minutes or less.

Separate administration within the context of the invention means theadministration of the PDE4 or the PDE3/4 inhibitor on the one hand andof the leukotriene receptor antagonist on the other hand in separatedosage forms within 12 hours or more.

“Combined use” in the context of the invention also includes apharmaceutical product comprising both the PDE4 or the PDE3/4 inhibitorand the leukotriene receptor antagonist as discrete separate dosageforms, in separate containers or e. g. in blisters containing both typesof drugs in discrete solid dosage units, preferably in a form in whichthe dosage units which have to be taken together or which have to betaken within one day are grouped together in a manner which isconvenient for the patient. Said pharmaceutical product itself or as apart of a kit may contain instructions for the simultaneous, sequentialor separate administration of the discrete separate dosage units, to apatient in need thereof.

By the expression “PDE4 inhibitor” is meant a selectivephosphodiesterase inhibitor, which inhibits preferentially the type 4phosphodiesterase when compared to other known types ofphosphodiesterase, e.g. type 1, 2, 3, 5 etc., whereby the compound has alower IC₅₀ (more potent) for the type 4 phosphodiesterase, such as wherethe IC₅₀ for PDE4 inhibition is about factor 10 lower compared to IC₅₀for inhibition of other known type of phosphodiesterase, e.g. type 1, 2,3, 5 etc.

Analogously, the expression “PDE3/4 inhibitor” is defined. Methods todetermine the activity and selectivity of a phosphodiesterase inhibitorare known to the person skilled in the art. In this connection it may bementioned, for example, the methods described by Thompson et al. (AdvCycl Nucl Res 10: 69-92, 1979), Giembycz et al. (Br J Pharmacol 118:1945-1958, 1996) and the phosphodiesterase scintillation proximity assayof Amersham Pharmacia Biotech.

By the expression “leukotriene receptor antagonist” is meant leukotrieneC4, leukotriene D4 and leukotriene E4 receptor antagonists, of which theleukotriene D4 receptor antagonists are preferred.

As possible PDE4 or PDE3/4 inhibitors within the meaning of the presentinvention may be mentioned, by way of example, those PDE4 or PDE3/4inhibitors which are named expressis verbis as an example, or describedor claimed generically in the following patent applications and patents:DE 1545687, DE 2028869, DE 2123328, DE 2315801, DE 2402908, DE 2413935,DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386,EP 0389282, EP 0393500, EP 0428302, EP 0435811, EP 0449216, EP 0459505,EP 0470805, EP 0490823, EP 0506194, EP 0510562, EP 0511865, EP 0527117,EP 0553174, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474,EP 0685475, EP 0685479, EP 0731099, EP 0736532, EP 0738715, EP 0748805,EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508,EP 0848000, JP 92234389, JP 94329652, JP 95010875, JP 98072415, JP98147585, U.S. Pat. Nos. 5,703,098, 5,739,144, WO 9117991, WO 9200968,WO 9212961, WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068,WO 9319720, WO 9319747, WO 9319749, WO 9319751, WO 9325517, WO 9402465,WO 9412461, WO 9420455, WO 9422852, WO 9427947, WO 9500516, WO 9501338,WO 9501980, WO 9503794, WO 9504045, WO 9504046, WO 9505386, WO 9508534,WO 9509623, WO 9509624, WO 9509627, WO 9509836, WO 9514667, WO 9514680,WO 9514681, WO 9517392, WO 9517399, WO 9519362, WO 9520578, WO 9522520,WO 9524381, WO 9527692, WO 9535281, WO 9535283, WO 9535284, WO 9600218,WO 9601825, WO 9606843, WO 9603399, WO 9611690, WO 9611917, WO 9612720,WO 9631486, WO 9631487, WO 9635683, WO 9636595, WO 9636596, WO 9636611,WO 9636625, WO 9636626, WO 9636638, WO 9638150, WO 9639408, WO 9640636,WO 9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345, WO 9712895,WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO 9722586, WO 9723457,WO 9723460, WO 9723461, WO 9724117, WO 9724355, WO 9725312, WO 9728131,WO 9730999, WO 9731000, WO 9732853, WO 9735854, WO 9736905, WO 9740032,WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO 9748697, WO 9804534,WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830,WO 9808841, WO 9808844, WO 9809946, WO 9809961, WO 9811113, WO 9814448,WO 9818796, WO 9821207, WO 9821208, WO 9821209, WO 9822453, WO 9831674,WO 9840382, WO 9845268, WO 9855481, WO 9856756, WO 9905111, WO 9905112,WO 9505113, WO 9906404, WO 9918095, WO 9931071, WO 9931090, WO 9947505,WO 9957115, WO 9957118, WO 9964414, WO 0001695, WO 0012501, WO 0026208,WO 0042017, WO 0042018, WO 0042019, WO 0042020, WO 0042034, WO 0119818,WO 0130766, WO 0130777, WO 0151470, WO 0206239, WO 0206270, WO 0205616and WO 0206238.

Exemplary PDE inhibitors are shown on the following pages with the aidof their formulae:

In the above formulae there is given neither any stereochemicalinformation nor are hydrogen atoms indicated [—O is accordingly —OH, >Nis >NH and —N is NH₂. Methyl groups, e.g. on the oxygen atoms, areindicated by lines].

Those PDE4 or PDE3/4 inhibitors are to be emphasized which are namedexpressis verbis as an example and/or claimed generically in the patentapplications or patents EP 0163965, EP 0389282, EP 0393500, EP 0435811,EP 0482302, EP 0499216, EP 0506194, EP 0510562, EP 0528922, EP 0553174,EP 0731099, WO 9319749, WO 9500516, WO 9501338, WO 9600218, WO 9603399,WO 9611690, WO 9636625, WO 9636626, WO 9723457, WO 9728131, WO 9735854,WO 9740032, WO 9743288, WO 9809946, WO 9807715, WO 9808841, WO 9821207,WO 9821208, WO 9821209, WO 9822453, WO 9831674, WO 9840382, WO 9855481,WO 9905111, WO 9905112, WO 9905113, WO 9931071, WO 9931090, WO 9947505,WO 9957115, WO 9957118, WO 9964414, WO 0001695, WO 0012501, WO 0042017,WO 0042018, WO 0042019, WO 0042020, WO 0042034, WO 0119818, WO 0130766,WO 0130777, WO 0151470 WO 0206239, WO 0206270, WO 0205616 and WO 0206238and the compounds with the following research codes: CDC-998, SH-636,D-4396, SCH-351591, IC-485, CC-1088 and KW-4490. Substances having goodoral availability are preferred here.

Preferred PDE4 or PDE3/4 inhibitors are the compounds with the researchcodes CDC-998, SH-636, D-4396, IC-485, CC-1088 and3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetra-hydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione[INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAM-FYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST] and3-Cyclopropylmethoxy-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST].

Particularly preferred PDE4 or PDE3/4 inhibitors are3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE].

As possible leukotriene receptor antagonists within the meaning of thepresent invention may be mentioned, by way of example,3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]-proplonic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxymethyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothlophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]-cyclopropyl]aceticacid [INN: MONTELUKAST].

Preferred leukotriene receptor antagonists areN-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN: ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].

Particularly preferred is2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].

In the context of the present invention, unless otherwise stated, apharmaceutically acceptable derivative of an active ingredient means apharmaceutically acceptable salt or solvate (e. g. hydrate), apharmaceutically acceptable solvate of such salt, a pharmaceuticallyacceptable N-oxide or a pharmaceutically acceptable salt or solvate ofthe latter.

Suitable pharmacologically tolerable salts here are on the one hand inparticular water-soluble and water-insoluble acid addition salts withacids such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid,butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid,fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid,stearic acid, toluenesulfonic acid, methanesulfonic acid or1-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether it is a mono- or polybasic acid anddepending on which salt is desired—in an equimolar quantitative ratio orone differing therefrom. Furthermore, the active compounds mentioned canalso be present as pure enantiomers or as enantiomer mixtures in anymixing ratio.

On the other hand, salts with bases are also suitable. Examples of saltswith bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,megiumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Certain of the active ingredients used in the present invention arecapable of existing in stereolsomeric forms. The invention encompassesall stereolsomers of the active ingredients and mixtures thereofincluding racemates. Tautomers and mixtures thereof of the activeingredients are also part of the present invention.

In accordance with the present invention, there is provided in a firstaspect a pharmaceutical composition comprising, in admixture, a firstactive ingredient which is selected from a PDE4 inhibitor, a PDE3/4inhibitor and their pharmaceutically acceptable derivatives, and asecond active ingredient which is selected from a leukotriene receptorantagonist and its pharmaceutically acceptable derivatives.

In a second aspect—which is an embodiment of the first aspect—there isprovided a pharmaceutical composition comprising, in admixture, a firstactive ingredient which is selected from CDC-998, SH-636, D-4396,IC-485, CC-1088 and3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-yl-carboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)-xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,and a second active ingredient which is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]-phenoxymethyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanilic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST],2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and their Pharmaceutically acceptablederivatives.

In a third aspect—which is another embodiment of the first aspect—thereis provided a pharmaceutical composition comprising, in admixture, afirst active ingredient which is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]-naphthyridine[INN: PUMAFENTRINE],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,and a second active ingredient which is selected from2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and its pharmaceutically acceptable derivatives.

In a forth aspect the invention provides a pharmaceutical productcomprising, in combination, a preparation of a first active ingredientwhich is selected from a PDE4 inhibitor, a PDE3/4 inhibitor and theirpharmaceutically acceptable derivatives, and a preparation of a secondactive ingredient which is selected from a leukotriene receptorantagonist and its pharmaceutically acceptable derivatives, forsimultaneous, sequential or separate use in therapy.

In a fifth aspect—which is an embodiment of the forth aspect—theinvention provides a pharmaceutical product comprising, in combination,a preparation of a first active ingredient which is selected fromCDC-998, SH-636, D-4396, IC-485, CC-1088 and3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzyiamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbomyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isolndole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureldobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,and a preparation of a second active ingredient which is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]-phenoxymethyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoicacid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanilic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothlophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST],2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and their pharmaceutically acceptablederivatives, for simultaneous, sequential or separate use in therapy.

In a sixth aspect—which is another embodiment of the forth aspect—theinvention provides a pharmaceutical product comprising, in combination,a preparation of a first active ingredient which is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,and a preparation of a second active ingredient which is selected from2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]-cyclopropyl]aceticacid [INN: MONTELUKAST] and its pharmaceutically acceptable derivatives,for simultaneous, sequential or separate use in therapy.

In a seventh aspect, the invention provides a kit comprising apreparation of a first active ingredient which is selected from a PDE4inhibitor, a PDE3/4 inhibitor and their pharmaceutically acceptablederivatives, a preparation of a second active ingredient which isselected from a leukotriene receptor antagonist and its pharmaceuticallyacceptable derivatives, and instructions for the simultaneous,sequential or separate administration of the preparations to a patientin need thereof.

In a eigth aspect—which is an embodiment of the seventh aspect—theinvention provides a kit comprising a preparation of a first activeingredient which is selected from CDC-998, SH-636, D-4396, IC-485,CC-1088 and3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN:CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazoidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)ocyclohexane-1-carboxylicacid [INN: CILOMILAST],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, apreparation of a second active ingredient which is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]-phenoxymethyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284J,5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanilic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAS ,2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and their pharmaceutically acceptablederivatives, and instructions for the simultaneous, sequential orseparate administration of the preparations to a patient in needthereof.

In a ninth aspect—which is another embodiment of the seventh aspect—theinvention provides a kit comprising a preparation of a first activeingredient which is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives, apreparation of a second active ingredient which is selected from2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and its pharmaceutically acceptable derivatives,and instructions for the simultaneous, sequential or separateadministration of the preparations to a patient in need thereof.

It has been found that the administration of active ingredientsaccording to the invention is advantageous because it results—incomparison to the administration of a single active ingredient from thePDE4 and PDE3/4 inhibitors or the leukotriene receptor antagonistsclass—in a reduced early allergic response as well as in a reduced lateinflammatory airway response.

The pharmaceutical composition of the present invention may be preparedby mixing the first active ingredient with the second active ingredient.

In the above-mentioned mixing process the first active ingredient andthe second active ingredient can

-   -   a) in a first step be mixed as such, afterwards be processed        with pharmaceutically acceptable auxiliaries and/or excipients        and finally pressed to tablets or caplets or    -   b) in a first step separately be processed with pharmaceutically        acceptable auxiliaries and/or excipients to give granules or        pellets containing each only one of the two active ingredients;        the pellets or granules for their part then can be mixed in an        appropriate ratio and either be pressed—optionally with further        pharmaceutically acceptable auxiliaries and/or excipients—to        give for example, tablets or caplets, or can be filled in more        or less loose form in capsules.

Therefore, in a tenth aspect of the present invention, there is provideda process for the preparation of a pharmaceutical composition whichcomprises mixing a first active ingredient which is selected from a PDE4inhibitor, a PDE3/4 inhibitor and their pharmacologically acceptablederivatives, with a second active ingredient which is selected from aleukotriene receptor antagonist and its pharmacologically acceptablederivatives.

In an eleventh aspect—which is an embodiment of the tenth aspect—thereis provided a process for the preparation of a pharmaceuticalcomposition which comprises mixing a first active ingredient which isselected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and3,5dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research-Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyrridine-4-carboxamide[Research-Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INNAROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]-naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-flouro-1-(4-fluorobenzyi)-1H-indol-3-yl]-2-oxoacetamide[Research-Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research-Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureldobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothiazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid [INN: CILOMILAST],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmacologically acceptable derivatives,with a second active ingredient which is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-(4-hydroxyphenyl)-1-methylethyl]-phenoxymethyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5-(E)-hexenyloxy]phenoxy]pentanoicacid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanilic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]-benzyl}-1-methylindol-5carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and their pharmacologically acceptablederivatives.

In an twelfth aspect—which is another embodiment of the tenthaspect—there is provided a process for the preparation of apharmaceutical composition which comprises mixing a first activeingredient which is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] and their pharmacologically acceptable derivatives,with a second active ingredient which is selected from2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] and its pharmacologically acceptablederivatives.

The present invention further provides the use of a pharmaceuticalcomposition, or pharmaceutical product according to the invention in themanufacture of a medicament for the prophylaxis and/or treatment of arespiratory tract disorder.

Respiratory tract disorders which may be mentioned are in particularallergen- and inflammation-induced bronchial disorders (bronchitis,obstructive bronchitis, spastic bronchitis, allergic bronchitis,allergic asthma, bronchial asthma, COPD, allergic, seasonal andperennial rhinitis), which can be treated by the combination accordingto the invention also in the sense of a long-term therapy (if desiredwith appropriate adjustment of the dosage of the individual componentsto the needs at the time, for example needs subject to seasonallyrelated variations).

In a further aspect the present invention provides a method of aneffective treatment of a respiratory tract disorder which can be treatedwith a PDE4 inhibitor, a PDE3/4 inhibitor or a leukotriene receptorantagonist comprising the separate, sequential or simultaneousadministration of i) a first amount of a PDE4 or a PDE3/4 inhibitor andii) a second amount of a leukotriene receptor antagonist, wherein thesum of the first and second amount is a therapeutically effectiveamount.

Said method also include a pharmaceutical product or kit containing aPDE4 or PDE3/4 inhibitor and a written description which discloses thatsaid PDE4 or PDE3/4 inhibitor can be administered together with aleukotriene receptor antagonist for the treatment of a respiratory tractdisorder which can be treated with a PDE4 inhibitor, a PDE3/4 inhibitoror a leukotriene receptor antagonist. Likewise, said method include apharmaceutical product or kit containing a leukotriene receptorantagonist and a written description which disdoses that saidleukotriene receptor antagonist can be administered together with a PDE4or PDE3/4 inhibitor for the treatment of a respiratory tract disorderwhich can be treated with a PDE4 inhibitor, a PDE3/4 inhibitor or aleukotriene receptor antagonist.

The active ingredients may, and indeed will, as part of thepharmaceutical composition, the pharmaceutical product or preparation,be used in admixture with one or more pharmaceutically acceptableauxiliaries and/or excipients.

The person skilled in the art is familiar on the basis of his/her expertknowledge with which excipients or auxiliaries are suitable for thedesired pharmaceutical composition, product or preparation. In additionto solvents, gel-forming agents, tablet excipients and other activecompound carriers, it is possible to use, for example, antioxidants,dispersants, emulsifiers, antifoams, flavor corrigents, preservatives,solubilizers, colorants or permeation promoters and complexing agents(e.g. cyclodextrins).

Within the meaning of the present invention, “use” is preferablyunderstood as meaning the oral administration of both activeingredients. Further methods of administration, which may be mentionedare the parenteral, intranasal, sublingual or rectal administration ofthe active ingredients. The active ingredients may as well beadministrated by inhalation or insufflation.

The pharmaceutical compositions or preparations according to theinvention are preferably in unit dosage form such as tablets, coatedtablets, pills, capsules, caplets, powders, granules, emulsions,suspensions or (sterile parenteral) solutions, metered aerosol or liquidsprays, drops ampoules transdermal patches, auto-injector devices orsuppositories; the active ingredient content advantageously beingbetween 0.1 and 95% and by appropriate choice of the excipients and theauxiliaries, it being possible to achieve a pharmaceuticaladministration form precisely tailored to the active ingredient(s)and/or to the desired onset of action (e.g. a sustained release form oran enteric form).

For the above-mentioned therapeutic uses the dosages administered will,of course, vary with the first and second active ingredients employed,the mode of administration, the treatment desired and the disorderindicated.

However, in general, satisfactory results will be obtained when thetotal daily dosage of first active ingredient(s), the PDE4 respectivelythe PDE3/4 inhibitors, when taken oral is in the range from 1-2000 μg/kgof body weight. In the case of the particularly preferred PDE4 inhibitorROFLUMILAST, the daily dosage is in a range from 1-20 μg/kg of bodyweight. The daily dosage for the particularly preferred PDE3/4 inhibitorPUMAFENTRINE is in a range from 300-1500 μg/kg of body weight.

The total daily dosage of the second active ingredient(s), theleukotriene receptor antagonists also can vary within a wide range. Inthe case of the particularly preferred leukotriene receptor antagonistMONTELUKAST, the daily dosage when taken oral is in a range from 50-400μg/kg of body weight.

PHARMACOLOGY

Objective:

To assess the additive or synergistic inhibitory effect of the selectivephosphodiesterase-4 inhibitor ROFLUMILAST combined with the leukotrienereceptor antagonist MONTELUKAST both orally administered 1 h beforeovalbumin (OVA) challenge on the early, mainly leukotriene-mediated(SRS-A=slow reacting substance of anaphylaxis) bronchoconstriction inanaesthetized, mechanically ventilated guinea pigs.

Animals:

Male Dunkin Hartley guinea pigs; body weight 200-250 g at sensitizationand 350-500 g when performing the experiments.

Drugs, Substances and Experimental Procedure:

Ovalbumin (OVA) was used as allergen for active sensitization.Therefore, 20 μg OVA together with 20 mg Al(OH)₃ suspended in 0.5 ml0.9% NaCl-solution (=saline) were administered i.p. to each animal on 2consecutive days. After 2-3 weeks the animals were challenged with asingle i.v. dose of 0.15 mg/kg OA suspended in saline. Drugs weresuspended in a 4%-methocel-solution and administered p.o. by gavage tothe conscious animals (n=10 animals per dose) 1 h before OVA-challenge:

-   -   1) ROFLUMILAST        (3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide)        at doses of 0.01, 0.1, 1.0, and 3.0 μmol/kg (0.004, 0.04, 0.4,        and 1.2 mg/kg)    -   2) MONTELUKAST sodium salt        2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic        acid sodium salt) at doses of 0.03, 0.10,0.17, and 0.5 μmol/kg        (0.018, 0.06, 0.1, and 0.3 mg/kg)    -   3) ROFLUMILAST at doses of 0.1, 0.3, and 1 μmol/kg (0.04, 0.12,        and 0.4 mg/kg) in combination with MONTELUKAST sodium salt 0.03        μmol/kg (0.018 mg/kg)

Controls received the drug-free methocel-solution 1 h beforeOVA-challenge as placebo (n=12). OVA-challenge and lung functionmeasurements were performed in anaesthetized and mechanically ventilatedanimals. Urethane was used for anesthesia and was injected i.p. at adose of 1.5 g/kg as 12.5% solution about 50 min before OVA-challenge. Toabolish spontaneous breathing, animals received 1.5 mg/kg i.v of themuscle relaxant pancuronium bromide about 14 min before OVA-challenge.To enhance the SRS-A-mediated bronchoconstriction, the animals werepretreated with: indomethacin 10 mg/kg i.v. 20 min before OVA-challengeto block the cyclooxygenase pathway and to enhance the production oflipoxygenase-mediators, mainly leukotrienes. Pyrilamine 2 mg/kg i.v. 6min before OVA-challenge to inhibit the bronchoconstrictor effect ofendogenously liberated histamine. Propranolol 0.1 mg/kg i.v. 5 minbefore OVA-challenge to abolish endogenous adrenergic tonus.Administration volume was 1 ml/kg for all i.v. injected compounds.

Measurement of the SRS-A-mediated Bronchoconstriction:

After injection of the muscle relaxant, the animals were ventilated at60 breaths/min, 7 ml/kg tidal volume and 40/60% inspiration/expirationratio using a small animal Ventilator. Dynamic lung compliance andairway conductance (=1/resistance) were calculated breath-by-breath fromtidal volume and pulmonary inflation pressure and from flow andpulmonary inflation pressure, respectively, using a PC-based softwareprogram for analysis, data acquisition and archiving of the respiratoryand cardiovascular parameters. The SRS-A-mediated bronchoconstrictionwas induced by i.v. injection of OVA. This was characterized by adecrease of compliance and conductance, which started about 1 min afterOVA-injection and reached a plateau at 70-90% decrease after 4-6 min.The time-effect curve for the delta-%-decrease of compliance andconductance was determined up to 12 min post challenge. Blood pressureand heart rate were monitored to control vitality.

Data Analysis:

The area under the time-delta-%-decrease curves (AUC) was determined foreach animal. On basis of the AUC-values, the inhibition of theSRS-A-induced decrease of compliance and conductance was calculated inreference to placebo. After eliminating drop-outs (Grubbs-test),dose-response curves were established, principally based on log-linearregression analysis, to determine ED₅₀-values. Pharmacodynamic effect ofROFLUMILAST combined with MONTELUKAST sodium salt was measured andcompared with the calculated effects according to G. Pöch [1]. Measuredand calculated ED₅₀-values were compared by an unpaired t-test forstatistical significant differences.

Results:

-   -   1) ROFLUMILAST inhibited decrease of airway conductance with an        ED₅₀ of 0.69 mg/kg (1.73 μmol/kg) and airway compliance with an        ED₅₀ of 0.58 μmol/kg (1.45 mg/kg) (FIGS. 1 and 2).    -   2) MONTELUKAST sodium salt inhibited decrease of airway        conductance with an ED₅₀ of 0.055 mg/kg (0.090 μmol/kg) and        airway compliance with an ED₅₀ of 0.053 μmol/kg (0.086 mg/kg)        (FIGS. 3 and 4).    -   3) ROFLUMILAST combined with MONTELUKAST sodium salt 0.018 mg/kg        (0.030 μmol/kg) inhibited decrease of airway conductance with an        ED₅₀ of 0.07 mg/kg (0.18 μmol/kg) and airway compliance with an        ED₅₀ of 0.08 μmol/kg (0.19 mg/kg) respectively. (FIGS. 5 and 6)    -   4) If one calculates the ED₅₀ values according to the method        described by G. Pöch [1] for ROFLUMILAST combined with        MONTELUKAST sodium salt 0.018 mg/kg (0.030 μmol/kg) on the basis        of the values given in 1) and 2) the ED₅₀ values come out as        follows: ED₅₀=0.15 mg/kg (0.38 μmol/kg) for airway conductance        and ED₅₀=0.11 (0.28 μmol/kg) for airway compliance (FIGS. 5 and        6).    -   5) Measured ED₅₀s are not significantly different from        calculated ED₅₀s.

SUMMARY

Inhibitory effects of ROFLUMILAST and MONTELUKAST sodium salt onSRS-A-induced bronchoconstriction are additive.

REFERENCES

G. Pöch. Quantitative Ermittlung potenzierender oder hemmenderKombinations-wirkungen gleichsinnig wirkender Pharmaka. 1981, Arzneim.Forsch./Drug Res. 31 (II), No. 7, 1135-1140

DESCRIPTION OF THE FIGURES

FIG. 1: Inhibition by ROFLUMILAST of OVA-induced Bronchoconstriction inSRS-A GPs (Conductance)

FIG. 2: Inhibition by ROFLUMILAST of OVA-induced Bronchoconstriction inSRS-A GPs (Compliance)

FIG. 3: Inhibition by MONTELUKAST sodium salt administered p.o. −1 h ofOVA-induced Bronchoconstriction in SRS-A GPs (Conductance)

FIG. 4: Inhibition by MONTELUKAST sodium salt administered p.o. −1 h ofOVA-induced Bronchoconstriction in SRS-A GPs (Compliance)

FIG. 5: Inhibition by ROFLUMILAST+MONTELUKAST sodium salt 0.018 mg/kgadministered p.o. −1 h of OVA-induced Bronchoconstriction in SRS-A GPs(Conductance)

FIG. 6: Inhibition by ROFLUMILAST+MONTELUKAST sodium salt 0.018 mg/kgadministered p.o. −1 h of OVA-induced Bronchoconstriction in SRS-A GPs(Compliance)

1. A pharmaceutical composition comprising, in admixture, a first activeingredient which is selected from a PDE4 inhibitor, a PDE3/4 inhibitorand their pharmaceutically acceptable derivatives, and a second activeingredient which is selected from a leukotriene receptor antagonist andits pharmaceutically acceptable derivatives.
 2. A pharmaceuticalcomposition according to claim 1, wherein the first and/or second activeingredient is in the form of a pharmaceutically acceptable salt,N-oxide, solvate of a salt or solvate of an N-oxide.
 3. A pharmaceuticalcomposition according to claim 1 which is a fixed oral combination.
 4. Apharmaceutical composition according to claim 1, wherein the firstactive ingredient is selected from CDC-998, SH-636, D-4396, IC-485,CC-1088,3,5-dichloro-4-[8-methoxy-2-(tri-fluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE], Tetrahydro-5-[4-methoxy-3-[(1S, 2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrimidone ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothioazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylicacid [INN: CILOMAST] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl) phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-[(4-hydroxyphenyl)-1-methylethyl]-phenoxy-methyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid [Research Code: ONO-4057], (2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 5. A pharmaceutical composition according toclaim 1, wherein the first active ingredient is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 6. A pharmaceutical composition according toclaim 5, wherein the first active ingredient is(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 7. A pharmaceuticalcomposition according to claim 5, wherein the first active ingredient is3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 8. A pharmaceuticalcomposition according to claim 5, wherein the second active ingredientis2-[1-[1(R)-[3-(2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 9. A method oftreating or preventing a respiratory tract disorder in a patientcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a pharmaceutical composition according to claim 1.10. A process for the preparation of a pharmaceutical composition asdefined in claim 1 which comprises mixing the first active ingredientwith the second active ingredient. 11-18. (Canceled)
 19. A kitcomprising i) a preparation of a first active ingredient which isselected from a PDE4 inhibitor, a PDE3/4 inhibitor and theirpharmaceutically acceptable derivatives, ii) a preparation of a secondactive ingredient which is selected from a leukotriene receptorantagonist and its pharmaceutically acceptable derivatives, and iii)instructions for simultaneous, sequential or separate administration toa patient in need thereof.
 20. A kit according to claim 19, wherein thefirst and/or second active ingredient is in the form of apharmaceutically acceptable salt, N-oxide, solvate of a salt or solvateof an N-oxide.
 21. A kit according to claim 19, wherein the first activeingredient is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 22. A kit according to claim 21, wherein thefirst active ingredient is(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 23. A kit accordingto claim 21, wherein the first active ingredient is3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 24. A kit accordingto claim 21, wherein the second active ingredient is2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 25. A method oftreating a respiratory tract disorder which can be treated with a PDE4inhibitor, a PDE3/4 inhibitor or a leukotriene receptor antagonistcomprising the separate, sequential or simultaneous administration of i)a first amount of a PDE4 or a PDE3/4 inhibitor and ii) a second amountof a leukotriene receptor antangonist, wherein the sum of the first andsecond amount is a therapeutically effective amount.
 26. A method oftreating a respiratory tract disorder which can be treated with a PDE3/4inhibitor or a leukotriene receptor antagonist comprising the separate,sequential or simultaneous administration of i) a first amount of aPDE3/4 inhibitor and ii) a second amount of a leukotriene receptorantangonist, wherein the sum of the first and second amount is atherapeutically effective amount.
 27. A pharmaceutical compositionaccording to claim 2 which is a fixed oral combination.
 28. Apharmaceutical composition according to claim 2, wherein the firstactive ingredient is selected from CDC-998, SH-636, D-4396, IC-485,CC-1088,3,5-dichloro-4-[8-methoxy-2-(tri-fluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide(Research Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothioazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylicacid [INN: CILOMAST] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl) phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-[(4-hydroxyphenyl)-1-methylethyl]-phenoxy-methyl]benzyloxy]benzenecarbox-imidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 29. A pharmaceutical composition according toclaim 3, wherein the first active ingredient is selected from CDC-998,SH-636, D-4396, IC-485, CC-1088,3,5-dichloro-4-[8-methoxy-2-(tri-fluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide[Research Code: SCH-351591],3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine[Research Code: V-11294A],N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide[Research Code: CI-1018], 4-(3,4-dimethoxyphenyl)thiazole-2-carboxamideoxime [Research Code: ORG-20241],3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN:AROFYLLINE],3-[3-(Cyclopentyloxy)-4-methoxybenzylamino]-1H-pyrazole-4-methanol,(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE],N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-281],N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide[Research Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine[INN: CIPAMFYLLINE],Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrimidone[INN: ATIZORAM],β-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide[Research Code: CDC-801], Methanesulfonic acid2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN:LIRIMILAST],(Z)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-imidazothioazolidin-4-one[INN: DARBUFELONE],cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane-1-carboxylicacid [INN: CILOMAST] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from3(S)-[2-(carboxyethyl)thio]-3-[2-(8-phenyloctyl) phenyl]-propionic acid[Research Code: SKF-S-106203],N-(ethoxycarbonyl)-4-[3-[4-[1-[(4-hydroxyphenyl)-1-methylethyl]-phenoxy-methyl]benzyloxy]benzenecarboximidamide[Research Code: BIIL-284],5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5(E)hexenyloxy]phenoxy]pentanoic acid [Research Code: ONO-4057],(2S,5S)-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran[Research Code: CMI-977],4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyricacid [Research Code: KCA-757],(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 30. A pharmaceutical composition according toclaim 2, wherein the first active ingredient is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 31. A pharmaceutical composition according toclaim 3, wherein the first active ingredient is selected from(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 32. A pharmaceutical composition according toclaim 30, wherein the first active ingredient is(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 33. A pharmaceuticalcomposition according to claim 31, wherein the first active ingredientis(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 34. A pharmaceuticalcomposition according to claim 30, wherein the first active ingredientis3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 35. A pharmaceuticalcomposition according to claim 31, wherein the first active ingredientis3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 36. A pharmaceuticalcomposition according to claim 30, wherein the second active ingredientis2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 37. A pharmaceuticalcomposition according to claim 31, wherein the second active ingredientis2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 38. (New) A kitaccording to claim 20, wherein the first active ingredient is selectedfrom(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] and3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST], and the second active ingredient is selected from(R)-N-[3-[5-(4-fluorobenzyl)thien-2-yl]-1-methyl-2-propynyl]-N-hydroxy-urea[INN: ATRELEUTON], 3-(1H-tetrazol-5-yl)oxanillic acid [INN:ACITAZANOLAST], N-hydroxy-N-[1-(benzothiophen-2-yl)ethyl]urea [INN:ZILEUTON],Cyclopentyl-3-{2-methoxy-4-[(2-methylphenylsulfonyl)carbamoyl]benzyl}-1-methylindol-5-carbamat[INN: ZAFIRLUKAST],8-[4-(4-phenylbutoxy)benzamido]-2-(tetrazol-5-yl)-4H-1-benzopyran-4-one[INN: PRANLUKAST] and2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST].
 39. A kit according to claim 38, wherein thefirst active ingredient is(−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylamino-carbonylphenyl)-benzo-[c][1,6]naphthyridine[INN: PUMAFENTRINE] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 40. A kit accordingto claim 38, wherein the first active ingredient is3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide[INN: ROFLUMILAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.
 41. A kit accordingto claim 38, wherein the second active ingredient is2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl)propylsulfanylmethyl]cyclopropyl]aceticacid [INN: MONTELUKAST] or a pharmaceutically acceptable salt, N-oxide,solvate of a salt or solvate of an N-oxide thereof.